ABSTRACT The limitation of current therapies for glioblastoma stems from their inability to reach tumor cells that insinuate themselves within neural structures. However, the obstacles to effective therapy match the known biological properties of neural stem cells (NSCs). Murine and human NSCs display an extensive tropism in vivo for neoplasms in the adult brain including tracking individual tumor cells that have escaped from the main tumor mass to infiltrate normal brain parenchyma and even homing to [unreadable]cancer stem cells[unreadable]. NSCs engineered ex vivo to produce therapeutic agents (e.g., genes that promote tumor apoptosis or lysis or that induce a host cytotoxic T cell response against the tumor) appear to mediate tumoricidal activity in such tumor masses and their disseminating microsatellite outgrowths, resulting in decreased tumor burden and prolonged survival in rodents. We isolated and characterized bone marrow derived neural stem cells (BM-NSCs) to study their function of migration, self-renewal, differentiation and engraftment. Understanding the mechanisms by which stem cells home to tumor cells and other areas of injury is important not only to understand basic stem cell biology but also to translate stem cell therapies for brain tumors and neurodegenerative disorders. During the past three years, we have begun to understand some of the molecules that mediate this homing [unreadable] e.g., SDF-1 secreted by the tumors, chemokines secreted from,endothelial cells, and receptors to tumor endothelium borne by the NSCs and CSCs. Optimizing stem cell therapies for brain tumors will depend on identifying the molecules and the mechanisms that underpin stem cell trafficking. We will study both cancer stem cell and bone marrow derived neural stem cell migration to: AIM 1: Test the hypothesis the CSC migration is dependent on paracrine SDF-1 expression. AIM 2: Test the hypothesis that VEGF induces secretion of an endothelium-derived soluble chemokine that attracts migration and invasion of CSC-derived glioma cells and that blocking VEGF signaling abrogates invasion of these CSC-derived cells. AIM 3: Test the hypothesis that migration of CSCs and BM-NSCs along or across endothelial cells is regulated by interaction of integrins &#945;2, &#945;6, and &#946;1, but not integrins &#945;4 and &#945;v as is the case with NSCs. AIM 4: Test the hypothesis that RGS3 and RGS16 (regulators of G-protein signaling) inhibit CXCR4 signaling during endothelial cell homing of CSCs as seen with NSCs. AIM 5: Test the hypothesis that A2B5 glial precursors from BM-NSC demonstrate tropism toward spontaneous glioblastoma in transgenic mice. We will test the hypothesis that blocking CXCR4 will inhibit BM-NSC migration to spontaneous tumors. We will also test the hypothesis that blocking &#945;6 integrin will inhibit transmigration of BM-NSC into spontaneous brain tumors after intravascular delivery.